1. Field of the Invention
This invention relates to the field of implantable medical devices, such as stents. More particularly, this invention is directed to coatings for devices, which include chemically bound polymers and/or oligomers of L-arginine.
2. Description of the Background
In the field of medical technology, there is frequently a necessity to administer a therapeutic substance locally. To provide an efficacious concentration to the treatment site, systemic administration of medication often produces adverse or toxic side effect for the patient. Local delivery is a preferred method in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Thus, local delivery produces fewer side effects and achieves more effective results. For the treatment of vascular occlusions, such as restenosis, stents are being modified to administer therapeutic substances locally. One method of medicating a stent is with the use of a polymer coating impregnated with a therapeutic substance. The coating allows for the sustained release of the substance at the treatment site. L-arginine, or polypeptide oligomeric derivatives or analogs thereof, for example, those containing 5 to 20 amino acid units are one example of a therapeutic substance that can be used in conjunction with a stent.
L-arginine is a known precursor of endothelium derived nitric oxide (NO). NO is synthesized from L-arginine, or its polymeric and/or oligomeric derivatives, by the enzyme NO synthase, a homodimeric flavo-hemoprotein that catalyzes the 5-electron oxidation of L-arginine to produce NO and L-citrulline. Among other therapeutic properties, NO relaxes vascular smooth muscle cells and inhibits the cells' proliferation. Inhibition of proliferation of vascular smooth muscle cells is believed to contribute to the reduction or elimination of restenosis.
U.S. Pat. No. 5,861,168 to Cooke et al. teach that NO activity is reduced after vascular injury. Cooke et al. also teach that administering L-arginine as the NO precursor helps to restore vascular NO activity in patients with endothelial vasodilator dysfunction due to restenosis.
However, introducing L-arginine into a stent coating by mere mechanical or physical blending with a polymer may be insufficient to achieve maximum therapeutic results. In other words, L-arginine will have a tendency to be released quickly when the stent coating is brought into contact with body fluids such as blood. The short residence time of the compound may be insufficient for the effective treatment of the patient. Accordingly, increasing the residence time of L-arginine at the implantation site is desired.
In addition, the amount of NO generated by L-arginine, or its polymers and/or oligomers, may be insufficient to achieve the best therapeutic results. Consequently, it is desirable to obtain an additional amount of NO upon decomposition of L-arginine, or its polymers and/or oligomers, caused by NO synthase oxygenase enzyme. Accordingly, it is desirable to incorporate an additional source of NO into the molecule of L-arginine, or its polymers and/or oligomers.